HIV Vaccines Should Mimic Body's Natural Response Say Researchers

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Main Category: HIV / AIDS
Also Included In: Immune System / Vaccines
Article Date: 16 Mar 2009 - 1:00 PDT

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New research led by a US team suggests that vaccines developed from a group of antibodies that occur naturally in the bodies of "slow progressing" HIV patients might be a better way to knock out the virus than focusing on a small number of engineered "super antibodies".

The study was led by Michel C Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology at the The Rockefeller University in New York and is published in the 15 March advanced online issue of Nature.

For the last 25 years, scientists have tried to develop a "magic bullet" HIV vaccine that rely on a small number of engineered "super antibodies" to stop the virus taking hold.

Nussenzweig, who is also a Howard Hughes Medical Institute investigator, and colleagues showed that patients infected with HIV in whom the virus progresses much more slowly, have a diverse group of antibodies produced naturally in dynamic response to the infection, that behave like a co-ordinated hunting pack to knock down the virus more effectively than their super antibody cousins fighting on their own.

They suggest that a "shotgun" approach, based on these naturally produced antibodies, might be a better way to develop an effective HIV vaccine than trying to engineer a super antibody "magic bullet".

As Nussenzweig explained, looking for a different approach, they tried to reproduce what happens in the patient:

"What's in the patient is many different antibodies that individually have limited neutralizing abilities but together are quite powerful," he said, adding that "this should make people think about what an effective vaccine should look like."

HIV's primary survival advantage is the ability of virus strains to mutate rapidly and thus stay one step ahead of the immune system and vaccine developers.

However, all HIV strains share one feature, they have a surface glycoprotein called gp140 that helps them to infect host cells. Earlier studies have shown there are four engineered antibodies that can stop the virus infecting human cells by blocking the action of gp140 in culture, but so far attempts to get the human body to produce these antibodies have failed.

In about 10 to 20 per cent of people infected with HIV, the virus progresses very slowly to disease because the memory B cells in their immune system produce high levels of antibodies specific to the virus. But nobody knows much about these antibodies and how effective they are.

Lead author Johannes Scheid, who was a visiting student in Nussenzweig's lab and is now a doctoral candidate, started examining naturally produced antibodies in six HIV infected patients whose immune systems appeared to be putting up a strong fight against the virus.

With the help of David D Ho and Jeffrey V Ravetch from the Rockefeller Center for Clinical and Translational Science, Scheid and colleagues took blood from these patients and isolated 433 antibodies that targeted gp140.

The researchers then mass-produced these 433 antibodies by cloning them, and then mapped which part of the gp140 protein each one attacked and how effective it was against the virus.

As a result, they found a new structure within the gp140 protein that is a potential new target for the antibodies. They called this new structure the "gp120 core", because it is in the same region as the CD4-binding site of another envelope glycoprotein gp120.

"It's the first time that anyone has defined what is really happening in the B cell response in these patients," said Scheid.

Nussenzweig said that what Sheid and colleagues did was find that each of the 433 antibodies had some way of attacking HIV, but each on its own did not do enough to knock it out.

Individually, these antibodies are not as strong as the four engineered super-antibodies, which Nussenzweig described as the "Famous Four" that vaccine developers are using.

But in high concentrations, and used as a group, the cloned antibodies appeared to act as a team, and just as able to knock out HIV in cell cultures as any single antibody studied to date, said Nussenzweig.

The natural antibodies alos recognized a range of HIV strains, suggesting another reason why used as a group, they may be more effective than a single super-antibody that only recognizes one part of a virus with a high rate of mutation.

The researchers believe their findings make a strong case for investigating potential vaccines that mimic the body's natural immune system response to HIV.

"Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals."
Johannes F. Scheid, Hugo Mouquet, Niklas Feldhahn, Michael S. Seaman, Klara Velinzon, John Pietzsch, Rene G. Ott, Robert M. Anthony, Henry Zebroski, Arlene Hurley, Adhuna Phogat, Bimal Chakrabarti, Yuxing Li, Mark Connors, Florencia Pereyra, Bruce D. Walker, Hedda Wardemann, David Ho, Richard T. Wyatt, John R. Mascola, Jeffrey V. Ravetch & Michel C. Nussenzweig.
Nature Published online 15 March 2009.
doi:10.1038/nature07930

Click here for Abstract.

Sources: Journal abstract, Rockefeller University.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
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